An improved practical synthesis of protected α-amino selenocarboxylates and its application to the synthesis of N-(α-aminoacyl)sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2009.07.080

An improved practical synthetic method was developed for the preparation of selenocarboxylates of amino acids through the reaction of the corresponding activated esters with sodium hydrogen selenide in alcoholic or aqueous medium. The protected α-amino se

Full text of DOI:10.1016/j.tetlet.2009.07.080

Tetrahedron Letters 50 (2009) 5585–5588
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An improved practical synthesis of protected
a-amino selenocarboxylates
and its application to the synthesis of N-(
a
-aminoacyl)sulfonamides
Xinghua Wu a, Yu Chen a, Longqin Hu a,b,
*
a Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
b The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved practical synthetic method was developed for the preparation of selenocarboxylates of
amino acids through the reaction of the corresponding activated esters with sodium hydrogen selenide
Received 29 June 2009
Revised 13 July 2009
Accepted 15 July 2009
Available online 18 July 2009
in alcoholic or aqueous medium. The protected
a-amino selenocarboxylates reacted readily with sulfonyl
azide to form N-( -aminoacyl)sulfonamides in high yields. The commonly used protecting groups in
a
amino acid and peptide chemistries are well tolerated under these reaction conditions. No protecting
groups are needed for the side chains of Arg, Met, Ser, Tyr, and Trp.
Ó 2009 Published by Elsevier Ltd.
N-Acylsulfonamide is an important functional group in organic
chemistry and is present in many biologically active molecules
including drugs. It has also been used in solid phase synthesis as
a linker to anchor to solid support and in chemoselective ligation
and bioconjugation reactions.1,2 N-Acylsulfonamide has a pKa
around 4–5 and excellent stability to chemical and enzymatic
hydrolyses, making it a suitable bioisostere for carboxylates3–5
and phosphates6 in drug design. N-Acylsulfonamide functionality
has been incorporated into investigational drugs and therapeutic
agents for Alzheimer’s disease,7 bacterial infection,8 osteoporoly-
sis,9 and cancer.10 For example, a small molecule ABT-737 with
an N-acylsulfonamide motif was shown to be a potent inhibitor
of Bcl-2/Bcl-xL interaction with BH3 domain only proteins11 and
is currently under clinical trials as a potential therapeutic agent
for the treatment of cancer.10
ily available. In addition, the procedure requires anhydrous condi-
tions that might limit its application as a general procedure for the
synthesis of N-acylsulfonamides.
Although first prepared in 1980s,18–20 selenocarboxylates
have not been successfully applied to chemoselective amidation
reaction until recently.21,22 Similar to thio acids, selenocarboxy-
lates can react with azido compounds forming amide bonds, but
in a more efficient manner and under milder conditions. We re-
cently reported this new selenocarboxylate/azide amidation
reaction21,23 and its application to the direct coupling of amino
acids with azides.24 We demonstrated that the selenocarboxy-
late/azide amidation was highly chemoselective and mild, and
worked very efficiently for electron-deficient azides including
aromatic azides substituted with an electron-withdrawing
group. We wanted to explore the use of the selenocarboxy-
N-Acylsulfonamides are most commonly prepared either from
direct acylation of the parent sulfonamide with acid chloride or
anhydride under basic conditions (e.g., trialkylamine, sodium
hydroxide),12,13 or from direct condensation of carboxylic acid in
the presence of coupling reagents such as EDC and CDI.8,14,15
Although these methods proved to be effective in many cases, they
do require strong coupling/condensation conditions (acyl chloride,
anhydride, CDI), strong basic conditions, and/or elevated reaction
temperature. Furthermore, the yields are often low due to the
incompatibility between the reaction conditions and the functional
groups present.16 Williams group recently reported a novel meth-
od for the preparation of N-acylsulfonamides utilizing amino thio-
acid/azide amidation reaction with excellent yields.17 However,
the procedure uses lithium trimethylsilyl thiolate that is not read-
late/azide amidation in amino acid chemistry to obtain N-(
aminoacyl)sulfonamides. To do so, we needed to overcome the
problem of the lack of efficient methods to prepare -amino
a-
a
selenocarboxylates that are prone to oxidation. Our goal, there-
fore, also included the development of a procedure that would
meet the following criteria: mild reaction conditions, compati-
bility with common protecting groups used in peptide chemistry
such as Fmoc, Boc, Cbz, and Trt; high yield of amidation, and
ease of handling. Previously, we reported a one-pot selenocarb-
a
oxylate/azide amidation procedure24 starting directly from N -
a
protected amino acids where the corresponding N -protected
amino selenocarboxylates were prepared in situ by the treat-
ment of the mixed anhydrides of amino acids with LiAlHSeH25
and subsequently reacted with azides to form the corresponding
amides. However, the preparation of LiAlHSeH required strict
anhydrous conditions and the reaction solvents were limited
to THF and Et2O. We would prefer aqueous or alcoholic reaction
* Corresponding author. Tel.: +1 732 445 5291; fax: +1 732 445 6312.
E-mail address: longhu@rutgers.edu (L. Hu).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.07.080

5586
X. Wu et al. / Tetrahedron Letters 50 (2009) 5585–5588
conditions for selenocarboxylate/azide amidation, since the rate
of selenocarboxylate/azide amidation increases with increasing
solvent polarity. Herein, we report an improved route to prepare
a
the N -protected amino selenocarboxylates by the reaction of
a
the activated ester of N -protected amino acids with sodium
hydrogen selenide (NaHSe) and its application in a one-pot
procedure to prepare N-(a-aminoacyl)sulfonamides using the
selenocarboxylate/azide amidation strategy.
In protic solvents, selenium was reported to react rapidly with
sodium borohydride (NaBH4) to generate sodium hydrogen sele-
nide (NaHSe) according to Eqs. 1 and 2.26 The selenium present
in such a solution is predominantly in the form of hydrogen sele-
nide ions (HSeꢀ, >99%) with <0.5% of selenide ions (Se2ꢀ). The
obtained sodium hydrogen selenide could be used directly to pre-
pare selenocarboxylates as its alcoholic or aqueous solution with-
out further purification.
4NaBH4 þ 2Se þ 7H2O ! 2NaHSe þ Na2B4O7 þ 14H2
NaBH4 þ Se þ 3EtOH ! NaHSe þ BðOEtÞ3 þ 3H2
ð1Þ
ð2Þ
Commercially available N-hydroxysuccinimide (OSu) esters of
a
N -protected amino acid were first used for our model reactions.
The active esters were mixed with a stoichiometric amount of
NaHSe, freshly prepared as mentioned above in a mixed solvent
of THF with water or 2-propanol, to generate the corresponding
selenocarboxylates in situ. Aliphatic selenocarboxylates were
generally thought to be less stable than aromatic selenocarboxy-
lates; to our surprise, we were able to monitor the formation of
N -protected amino selenocarboxylates using LC–MS in ESꢀ
a
mode. As shown in a representative analysis in Figure 1, the ma-
jor peak at 3.08 min in the UV trace (Fig. 1A) is Z-Gly-SeH, which
has an observed m/z of the most abundant molecular ion
[MꢀH]ꢀ at 271.9 shown in the extracted ion chromatogram
(Fig. 1B). The isotopic pattern of the molecular ion is character-
istic of selenium-containing compounds (Fig. 1C): selenium has
six naturally occurring isotopes, five of which are stable, includ-
ing 74Se (0.89%), 76Se (9.37%), 77Se (7.63%), 78Se (23.79%), and
80Se (49.61%), along with the fission products 79Se and 82Se
(8.73%) that are considered stable due to their very long half-
lives.27 Thus, using LC–MS, we were able to observe that NaHSe
Figure 1. LC–MS analysis of the reaction between Z-Gly-OSu and sodium hydrogen
selenide. Shown are the UV trace at 280 nm (A); extracted ion chromatogram using
271.9, the most abundant molecular ion—H (B); and ESꢀ mass spectrum of Z-Gly-
SeH (C).
a
reacted rapidly with N -protected amino acid–OSu esters to pro-
duce the corresponding selenocarboxylates. Most of the reactions
were generally complete within 0.5 h at 0 °C. However, for steri-
cally hindered amino acid–OSu esters, such as that of isoleucine,
valine, and threonine, the reactions were slower and required
room temperature to reach completion.
in 92% yield (Table 1, entry 1), indicating that the reaction could
be carried out under aqueous conditions. When Fmoc-Ile-OSu
was used to react with NaHSe, room temperature, instead of
0 °C, was required to complete the selenocarboxylation, suggest-
ing the presence of steric hindrance of Ile side chain. However,
once the Fmoc-Ile-SeNa was formed, it quickly reacted with
p-toluenesulfonyl azide to provide N-(Fmoc-isoleucyl)sulfon-
amide in an excellent yield (Table 1, entry 4). This indicated that
the steric hindrance of selenocarboxylates did not play a signif-
icant role in the step of amidation, which is consistent with our
previous observation that the rate of selenocarboxylate/azide
amidation primarily depends on the electronic properties of
the azide.24 Furthermore, the indole unit of tryptophan did not
need protection and was well tolerated without affecting the
yield of amidation reaction (Table 1, entry 6).
After completion of selenocarboxylation as monitored by LC–MS,
a solution of p-toluenesulfonyl azide in THF was added via syringe.
The amount of protected
a-amino selenocarboxylates generated
was slightly in excess (1.2 equiv) relative to the azide used. The
reactions started immediately with the precipitation of gray sele-
nium and the formation of nitrogen gas, and were complete within
a
2 h at room temperature to form the corresponding N-(N -pro-
tected aminoacyl)sulfonamides. As shown in Table 1, Z, Boc, Fmoc,
and Trt protecting groups were all well tolerated under our condi-
a
tions and excellent yields of N-(N -protected aminoacyl)sulfona-
mides were obtained. We also found that the hydroxy group of
tyrosine and threonine did not need to be protected. No significant
intermolecular esterification was observed under the present reac-
tion conditions and the desired N-(a-aminoacyl)sulfonamides were
obtained in excellent yields (Table 1, entries 2 and 3).
In summary, a convenient and high-yield synthesis of seleno-
carboxylates of amino acids was developed and applied to the
synthesis of N-(a-aminoacyl)sulfonamides. This strategy can also
be applied to the synthesis of other electron-deficient amides
that are usually difficult to prepare via conventional amidation
methods due to the poor nucleophilicity of the corresponding
amines.
Furthermore, we prepared an aqueous solution of NaHSe
according to Eq. 1 and reacted it with Z-Gly-OSu in 50% aqueous
THF to produce Z-Gly-SeNa. Subsequent amidation with p-tolu-
enesulfonyl azide afforded the desired N-(Z-glycyl)sulfonamide

X. Wu et al. / Tetrahedron Letters 50 (2009) 5585–5588
5587
Table 1
Synthesis of N-(N -protected aminoacyl)sulfonamides via selenocarboxylate/azide amidationa
a
O
O O
S
O
N3 SO2
O
NaHSe
R
N
R
OSu
H
R
SeNa
Entry
1
R
Amino acid-activated ester
Z-Gly-OSu
Product
Yieldb (%)
95 (92c)
O
S
H
H
O
N
Cbz Gly N
O
O
O
H
N
O
O
S
O
H
2
Z-Tyr-OSu
92 (90c)
Cbz Tyr N
OH
O
S
O
H
91d
H
N
3
Fmoc-Thr-OSu
Fmoc Thr N
O
O
OH
O
S
H
H
N
4
Fmoc-Ile-OSu
92d
Fmoc Ile N
O
O
O
O
S
O
H
5
Fmoc-Met-OSu
92
H
N
Fmoc Met N
O
O
O
O
S
O
S
O
H
N
H
6
Fmoc-Trp-OSu
Fmoc-His(Trt)-OSu
Boc-Phe-OSu
90
93
95
Fmoc Trp N
NH
O
S
O
H
N
H
O
7
Fmoc His N
Trt
Ph
Ph
Ph
O
N
N
H
N
O
O
S
O
H
8
Boc PheN
O
a
a
Conditions: NaHSe (1.2 equiv) and N -protected amino acid–OSu (1.2 equiv) in THF/2–PrOH, 0 °C, then p-toluenesulfonyl azide(1.0 equiv).
b
c
Isolated yield under standard conditions unless noted otherwise in c and d.
NaHSe (1.2 equiv) and N -protected amino acid–OSu (1.2 equiv) in THF/H2O, 0 °C, then p-toluenesulfonyl azide (1.0 equiv).
NaHSe (1.2 equiv) and N -protected amino acid–OSu (1.2 equiv) in THF/2-PrOH, rt, then p-toluenesulfonyl azide (1.0 equiv).
a
d
a

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X. Wu et al. / Tetrahedron Letters 50 (2009) 5585–5588
10. Kang, M. H.; Reynolds, C. P. Clin. Cancer Res. 2009, 15, 1126–1132.
Acknowledgments
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We gratefully acknowledge the financial support of a research
grant from the Elsa U. Pardee Foundation and a research scholar
grant from the American Cancer Society. We thank Professor
Lawrence Williams, Professor Spencer Knapp, and Dr. Yiyu Ge for
helpful discussions.
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